Testosterone replacement may lower stroke, MI and death rate in older men.

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Normalization of total testosterone (TT) levels using testosterone replacement therapy (TRT) is associated with lower all-cause mortality, and fewer MIs and ischaemic strokes in men without a history of MI or stroke, according to an observational study.

Other retrospective studies, multiiple meta-analyses, and a few small prospective studies have presented conflicting results on the effects of TRT, and a small randomized prospective study was stopped early due to an increased incidence of CV events with TRT.

Testosterone replacement therapy (TRT) appeared to lower the risk for myocardial infarction, stroke and death in androgen-deficient older men whose testosterone levels were normalized by the treatment, a retrospective study found.

The trial, which included just over 83,000 male veterans with documented low total testosterone and no history of stroke or MI, is the largest observational study with the longest follow up to examine the impact of testosterone therapy on cardiovascular risk in an elderly population, researchers said.

Compared to TRT-treated men who did not achieve testosterone normalization, those who did saw a 47% mortality benefit, a 18% MI benefit and a 30% stroke benefit (hazard ratio for death = 0.53, 95% CI 0.50 to 0.55; HR for MI =0.82, 95% CI 0.71 to 0.95; HR for stroke = 0.70, 95% CI 0.51 to 0.96), researcher Rajat S. Barua, MD, PhD, of the Kansas City VA Medical Center told MedPage Today.

All-cause mortality, MI, and stroke rates were also significantly lower in men with normalized testosterone levels following TRT, compared to men with hypogonadism who did not receive testosterone therapy (HR for mortality: 0.44; 95% CI 0.42 to 0.46; HR for MI: 0.76, 95% CI 0.63 to 0.93; and HR for stroke: 0.64, 95% CI 0.43 to 0.96).

'Surprised By Findings'

Findings from recent studies -- mostly retrospective -- examining the impact of TRT on cardiovascular outcomes and death have been mixed, with some suggesting a positive association or little impact and others showing cause for concern.

"We were somewhat surprised by the findings, which suggest that older men without a history of MI or stroke who have signs and symptoms of hypogonadism and evidence of low T on two tests may benefit from testosterone treatment," Barua said. "I would argue that we can safely use this treatment in appropriately identified patients who also have appropriate follow up."

The analysis included 83,010 men with documented low T and no history of stroke and MI treated at 140 VA hospitals across the country over a 14-year period, Barua said. Because of a lack of standardization from lab to lab regarding test assays and testosterone reference ranges, the researchers classified each test result as low or normal based on its respective laboratory reference range.

"This approach permitted inclusion of testosterone values obtained using different assay methods and minimized the investigator bias likely introduced by an arbitrary cut-off value," they wrote.

Limiting the study cohort to men without a history of MI or stroke prior to initiation of TRT reduced bias associated with cardiovascular outcomes.

By utilizing propensity score-weighted Cox proportional hazard models, the researchers were able to compare the association of TRT with all-cause mortality, MI, stroke, and a composite of these endpoints.

Study limitations included the potential for unmeasured confounding or hidden bias and the lack of randomization and data on indications for treatment in men identified as having hypogonadism.

"Despite the limitations associated with a retrospective study, our study has the advantages of having a large subject population with extensive follow-up. Our findings show that effective TRT is associated with lower rates of cardiovascular events in men without previous history of MI or stroke, in whom low total testosterone levels are documented and effective TRT is provided," the researchers wrote, adding that the safety and outcomes of TRT in other populations remains unknown.

'TOM' Trial Findings Still a Concern

The findings appear to contradict one of the few prospective randomized studies examining TRT in older men -- the Testosterone in Older Men (TOM) trial. The trial was stopped early at 6 months due to increased cardiovascular events in men receiving testosterone therapy.

Barua noted that the TOM trial had significant limitations, including a small sample size (n=209 men) and a high prevalence of diabetes, hypertension, and dyslipidemia among the cohort.

But neurologist Ralph Sacco, MD, of the University of Miami Miller School of Medicine, who commented on the newly published observational trial for MedPage Today, said that despite these limitations, the TOM trial findings cannot be ignored.

Sacco is a past president of the American Heart Association.

"I would rely more on a randomized trial than retrospective data, even though the (newly published) trial findings are intriguing," he said. "In my mind there is still not enough evidence to determine if TRT increases or decreases cardiovascular risk in this population."

The research was funded by the Kansas City Veterans Administration Medical Center and the Midwest Biomedical Research Foundation.

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